The discovery of new reactivity principles has led to major advances in the efficient synthesis of diverse molecular architectures. Classical examples include the classification of a significant portion of organic reactivity in terms of nucleophilicity and electrophilicity;the discovery of pericyclic processes and the subsequent recognition of the consequences of concertedness on stereospecificity;and the development of conformational analysis and the study of its impact on reactivity. Recent examples include breakthroughs in organometallic chemistry, typified by cross-coupling and olefin-metathesis reactions, which proceed with broad substrate scope and functional group tolerance. Each of these advances has impacted our CMLD research and diversity synthesis in general. In enantioselective synthesis, numerous advances in chiral auxiliary-based and asymmetric catalytic methods have broadened the range of chiral building blocks available to synthetic chemists far beyond the limited pool provided by Nature. Highly stereoselective reagents and catalysts have also enabled the elaboration of chiral building blocks into stereochemically and skeletally diverse small molecules.[1] Several important reactivity principles have been exploited in order to achieve enantioselectivity in catalytic processes. The most prevalent of these involves association of a chiral ligand framework to a metal-based catalyst, which may be used in selective organometallic, oxidative, or Lewis acid-mediated transformations.[2] However, alternative approaches have also proven effective, including multifunctional, chiral phase-transfer, and nucleophilic catalysts. The emergence of organocatalysis as a discrete strategy in organic chemistry has been tied closely to the recent development of secondary amines as catalytic promoters of enantioselective addition reactions via enamines or iminium ions.[3,4] These advances are at the heart of our CMLD. Another important, promising strategy for asymmetric catalysis involves use of small-molecule chiral hydrogenbond donors. Efforts spearheaded by our group and several others have led to the discovery that low molecular weight synthetic molecules possessing distinct hydrogen-bond donor motifs associated with complementary functional and/or structural frameworks catalyze an array of C-C and C-heteroatom bondforming reactions with high enantioselectivity and broad substrate scope.[5] Although the vast majority of developments in hydrogen bonding catalysis have materialized only within the last five years, the foundations of this subfield of organocatalysis were laid by research in various disciplines over the past several decades.[6] Dual hydrogen bond donors such as ureas, thioureas, guanidinium and amidinium ions, and bisphenols, have been studied in detail in the context of electrophile activation. Activation of carbonyl derivatives using chiral Hbond donors of this type has been applied in asymmetric catalysis of mechanistically diverse transformations, including 1,2-addition, acyl transfer, 1,4-addition, and cycloaddition reactions. As demonstrated in a recent study carried out in our group, these catalysts operate via simultaneous donation of both H-bonds to stabilize the developing charge of a forming tetrahedral intermediate, in a manner resembling the well-known oxy-anion hole concept prevalent in enzymatic catalysis.[7] These same classes of dual H-bond donors are also well studied in the sensing and molecular recognition fields for their properties as anion-binding agents.[8,9] Selective binding of halides, carboxylates, sulfonates, and phosphates has been demonstrated and quantified in a variety of urea and thiourea derivatives. The proven ability of chiral ureas and thioureas to serve as effective catalysts and as anion-binding agents raises the interesting possibility of their application in enantioselective reactions involving anion binding or abstraction. Scheme 1 illustrates this concept in two different contexts. In the first, the catalyst abstracts a leaving group from an electrophile, generating a highly reactive cationic species that is subsequently trapped by a nucleophile to provide a chiral product. Enantioselectivity results from electrostatic interactions between the thiourea/anion complex and the cation, reinforced by secondary stabilizing interactions involving the catalyst and substrate. The second scenario involves catalyst binding a weak Bronsted acid, effectively enhancing its acidity. Protonation of a basic substrate by the activated acid affords an analogous ion pair intermediate, and nucleophilic trapping of this cationic species results in the formation of a chiral product. During the previous funding period we have established the viability of both of the above strategies in the context of highly enantioselective and synthetically interesting reactions (Scheme 2), some of which are driving library development activities of our CMLD (Overview and Projects 1 and 2). These advances are outlined in the Progress Report section of this proposal. Communication of stereochemical information through counterion interactions is well precedented in chiral phase-transfer catalysis, and has recently been demonstrated in the context of asymmetric counterion-directed catalysis.[11,12] However, to the best of our understanding, the modes of substrate activation shown in Scheme 1 are fundamentally new to asymmetric catalysis. Recognition of such reactivity patterns raises the possibility of affecting enantioselective transformations across a broad spectrum of reactive cationic intermediates (Figure 2). In addition to further clarification of the important reactivity principles underlying these transformations, realization of this objective could be a driver of our future library development efforts. This will be our focus during the next funding period.